ABSTRACT The Wisconsin Registry for Alzheimer?s Prevention (WRAP) is a longitudinal observational cohort study of 1,561 middle-aged persons with and without a parental family history of AD. The study conducts cognitive, laboratory and now molecular neuroimaging assessments at 2-year intervals to identify the health, lifestyle and genetic risk factors that influence biomarker expression of AD in persons who are currently asymptomatic, but are at an increased risk of developing the disease. This study will combine the data collected over the past 15 years with new biomarker, cognitive, lifestyle and laboratory data collected with this renewal to establish longitudinal trajectories and describe the neurobiology of preclinical AD. Currently the temporal course of preclinical AD, and the factors that influence change during the decade before the development of clinical symptoms are unknown. This information is essential for the development of clinical trials evaluating disease- modifying therapies designed to delay the onset or slow the progression of AD. In the prior funding period we: Began to develop and apply new approaches to identify mild cognitive decline using internal robust norms; Developed polygenic risk scores associated with health and cognitive phenotypes; Demonstrated that lifestyle and health features in midlife impact overall brain health and specific AD pathophysiologic markers and thus may confer resilience to cognitive decline and AD pathology; Demonstrated differential rates of cognitive decline by AD biomarker pathology status in a subset of WRAP using cerebrospinal fluid (CSF) and/or imaging markers of amyloid, tau, neurodegeneration and vascular disease; and established participation in a consortium of several adult children cohorts, which has enhanced data sharing and will improve rigorousness in research using confirmatory methodologies across large cohorts. WRAP is now uniquely positioned to address major knowledge gaps in the next funding period: A) develop and validate longitudinal change standards for identifying when an individual?s cognitive decline exceeds the pace of normal aging; B) identify modifiable and nonmodifiable characteristics that predict midlife cognitive trajectories and development of abnormal cognition (e.g., MCI or dementia); C) understand the early effects of the two most common diseases causing cognitive dysfunction in this age group?1) the dual AD pathologies of amyloid and tau (via CSF Ab42 and ptau181, and/or molecular PET imaging of amyloid with [C-11]PiB and tau with [F-18]MK6240) and 2) neurovascular pathology (with novel measures of cerebral arterial and venous pulsatility and flow), on domain- specific cognitive trajectories and abnormal cognitive outcomes; and D) elucidate the effect of modifiable and nonmodifiable features on the relationship between AD and vascular pathology and cognition.